New sulfonylaminobenzamide compounds

ABSTRACT

The present invention relates to a new compound of formula (I) wherein the variables have the meaning as indicated in the claims; or an enantiomer or salt thereof. The compounds of formula (I) are useful in the control of parasites, in particular endoparasites, in and on vertebrates.

The present invention relates to novel sulfonylaminobenzamide compoundsand their use in the control of endoparasites, for example heartworms,in warm-blooded animals.

Heartworm (Dirofilaria immitis) is a parasitic roundworm that is spreadfrom host to host through the bites of mosquitoes. The definite host isthe dog but it can also infect cats and other warm-blooded animals.Although commonly being called “heartworm” the adult worms actuallyreside in the pulmonary arterial system (lung arteries) for the mostpart, and the primary effect on the health of the animal is damage tothe lung vessels and tissue. Occasionally, adult heartworms migrate tothe right heart and even the great veins in heavy infections. Heartworminfection may result in serious disease for the host.

Heartworm infections may be combated with arsenic-based compounds; thetreatment is time-consuming, cumbersome and often only partlysuccessful. Accordingly, the main focus is on the prevention ofheartworm infections. Heartworm prevention is currently performedexclusively by year round periodical administration of a macrocycliclactone such as ivermectin, moxidectin or milbemycin oxim to the dog,cat or else warm-blooded animal. Unfortunately, upcoming resistancy ofDirofilaria immitis against macrocyclic lactones has been observed incertain parts of the USA. Accordingly, there is a strong need forfinding new classes of compounds which are effectively controllingheartworm infections either by way of prophylaxis or by direct killingof the different stages of heartworms. It now has been foundsurprisingly that a group of novel sulfonylaminobenzamide compoundseffectively controls endoparasites including heartworms effectively onwarm-blooded animals.

The present invention therefore according to one embodiment concerns acompound of formula

or a salt or an enantiomer thereof, wherein X is O, S, NR²C(O), C(CN) orCH═CH,R⁰ is H, C₁-C₄-alkyl or hydroxyl;n is 0 or 1,each R is independently halogen; C₁-C₆-alkyl; C₁-C₆-haloalkyl;C₃-C₆-cycloalkyl; C₃-C₆-halocycloalkyl; amino; N-mono- orN,N-di-C₁-C₄-alkylamino; hydroxy; C₁-C₆-alkoxy; C₁-C₆-haloalkoxy;C₁-C₆-alkylthio; C₁-C₆-haloalkylthio; C₁-C₆-alkyl-sulfinyl;C₁-C₆-haloalkylsulfinyl; C₁-C₆-alkylsulfonyl; C₁-C₆-haloalkylsulfonyl;SF₅; tri-C₁-C₄-alkylsilyl; C₁-C₆-alkoxycarbonyl; aminocarbonyl; N-mono-or N,N-di-C₁-C₆-alkylaminocarbonyl; aminosulfonyl; N-mono- orN,N-di-C₁-C₆-alkylaminosulfonyl; N—C₁-C₆-alkylsulfonylamino;C₁-C₆-alkoxycarbonylamino; N—C₁-C₄-alkyl-N—C₁-C₆-alkoxycarbonylamino;cyano; nitro; or C₃-C₆-heterocyclyl which is unsubstituted orsubstituted by halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cyclolalkyl,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, amino, cyano or nitro;m is an integer from 0 to 4;each R¹ is independently halogen; C₁-C₆-alkyl; C₁-C₆-haloalkyl;C₃-C₆-cycloalkyl; C₃-C₆-halocycloalkyl; C₁-C₆-alkoxy; C₁-C₆-haloalkoxy;C₁-C₆-alkylthio; C₁-C₆-haloalkylthio; C₁-C₆-alkyl-sulfinyl;C₁-C₆-haloalkylsulfinyl; C₁-C₆-alkylsulfonyl; C₁-C₆-haloalkylsulfonyl;SF₅; amino;N-mono- or N,N-di-C₁-C₆-alkylamino; tri-C₁-C₄-alkylsilyl;C₁-C₆-alkoxycarbonyl; aminocarbonyl; N-mono- orN,N-di-C₁-C₆-alkylaminocarbonyl;N,N-di-C₁-C₄-alkylamino-C₁-C₄-alkylaminocarbonyl; aminosulfonyl; N-mono-or N,N-di-C₁-C₆-alkylaminosulfonyl; N—C₁-C₆-alkylsulfonylamino;C₁-C₆-alkoxycarbonylamino; N—C₁-C₄-alkyl-N—C₁-C₆-alkoxycarbonylamino;cyano; nitro; hydroxy; B(OH)₂; or phenyl, benzoyl, C₃-C₆-heterocyclyl,C₃-C₆-heterocyclyloxy or C₆-C₈-benzoheterocyclyl, which is eachunsubstituted or substituted by halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₃-C₆-cycloalkyl; C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, amino, cyano or nitro;andr is an integer of from 1 to 4.

The invention also provides a composition comprising a compound offormula (I), or a salt or enantiomer thereof, and at least one carrier,for example a surfactant, a solid diluent and/or a liquid diluent.

In one embodiment, this invention also provides a composition forcontrolling parasites, in particular endoparasites, comprising abiologically effective amount of a compound of formula (I), or a saltthereof, and at least one additional component selected from the groupconsisting of a surfactant, a solid diluent and a liquid diluent, saidcomposition optionally further comprising a biologically effectiveamount of at least one additional pharmaceutically or veterinary activecompound or agent.

This invention also provides a method for controlling parasitescomprising contacting the parasites or their environment with apharmaceutically or veterinary effective amount of a compound of formula(I), an enantiomer or a salt thereof, (e.g., as a composition describedherein). This invention also relates to such method wherein theparasites or their environment are contacted with a compositioncomprising a pharmaceutically or veterinary effective amount of acompound of formula (I), an enantiomer or a salt thereof, and at leastone additional component selected from the group consisting of asurfactant, a solid diluent and a liquid diluent, said compositionoptionally further comprising a pharmaceutically or veterinary effectiveamount of at least one additional pharmaceutically or veterinary activecompound or agent.

This invention also provides a method for protecting an animal from aparasitic pest comprising administering to the animal a parasiticidallyeffective amount of a compound of formula (I), an enantiomer or a saltthereof.

DETAILS OF THE INVENTION

In the above recitations, the term “alkyl”, used either alone or incompound words such as “alkylthio”, “haloalkylthio”, “haloalkyl”,“N-alkylamino”, “N,N-di-alkyamino and the like includes straight-chainor branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, n-, iso-,sec.- or tert.-butyl or the different pentyl or hexyl isomers.

The term “alkoxy” used either alone or in compound words such as“haloalkoxy”, “alkoxycarbonyl” includes, for example, methoxy, ethoxy,n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxyisomers. “Alkylthio” includes branched or straight-chain alkylthiomoieties such as methylthio, ethylthio, and the different propylthio,butylthio, pentylthio and hexylthio isomers.

“Alkylsulfinyl” includes both enantiomers of an alkylsulfinyl group.Examples of “alkylsulfinyl” include CH₃S(O)—, CH₃CH₂S(O)—,CH₃CH₂CH₂S(O)—, (CH₃)₂CHS(O)— and the different butylsulfinyl,pentylsulfinyl and hexylsulfinyl isomers.

Alkylcarbonyl” denotes a straight-chain or branched alkyl moietiesbonded to a C(═O) moiety. Examples of “alkylcarbonyl” include CH₃C(═O)—,CH₃CH₂CH₂C(═O)— and (CH₃)₂CHC(═O)—. Examples of “alkoxycarbonyl” includeCH₃OC(═O)—, CH₃CH₂OC(═O), CH₃CH₂CH₂OC(═O)—, (CH₃)₂CHOC(═O)— and thedifferent butoxy- or pentoxycarbonyl isomers, for exampletert.-butoxycarbonyl (Boc). Examples of “alkoxycarbonylamino” orN-alkoxycarbonyl,N-alkylamino include tert.-butoxycarbonylamino andN-tert.-butoxycarbonyl,N-methylamino. Examples of “N-mono- orN,N-di-alkylaminocarbonyl”” include “N-methylaminocarbonyl”,“N-ethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl,N,N-di-methylaminocarbonyl or N,N-di-ethylaminocarbonyl. Examples of“alkylcarbonylamino” include “, “methylcarbonylamino” or“ethylcarbonylamino”.

Examples of “alkylsulfonyl” include CH₃S(O)₂—, CH₃CH₂S(O)₂—,CH₃CH₂CH₂S(O)₂—, (CH₃)₂CHS(O)₂—, and the different butylsulfonyl,pentylsulfonyl and hexylsulfonyl isomers. Examples of “N-mono- orN,N-di-alkylaminosulfonyl”” include “N-methylaminosulfonyl”,“N-ethylaminosulfonyl, N-methyl-N-ethylaminosulfonyl,N,N-di-methylaminosulfonyl or N,N-di-ethylaminosulfonyl. Examples of“alkyl-sulfonylamino” include”, “methylsulfonylamino” or“ethylsulfonylamino”.

“Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl. The term “alkylcycloalkyl” denotes alkyl substitution ona cycloalkyl moiety and includes, for example, ethylcyclopropyl,i-propylcyclobutyl, 3-methylcyclopentyl and 4-methycyclohexyl.

The term “halogen”, either alone or in compound words such as“haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further,when used in compound words such as “haloalkyl”, said alkyl may bepartially or fully substituted with halogen atoms which may be the sameor different. Examples of “haloalkyl” include F₃C—, ClCH₂—, CF₃CH₂— andCF₃CCl₂—. The terms “halocycloalkyl”, “haloalkoxy”, “haloalkylthio”, andthe like, are defined analogously to the term “haloalkyl”. Examples of“haloalkoxy” include CF₃O—, CF₃CF₂—O—, CF₃CH₂O—, CCl₃CH₂O—, CF₃CHFCF₂O—and HCF₂CH₂CH₂O—; and Examples of “haloalkylthio” include CCl₃S—, CF₃S—,CCl₃CH₂S— and ClCH₂CH₂CH₂S—. Examples of “haloalkylsulfinyl” includeCF₃S(O)—, CCl₃S(O)—, CF₃CH₂S(O)— and CF₃CF₂S(O)—. Examples of“haloalkylsulfonyl” include CF₃S(O)₂—, CCl₃S(O)₂—, CF₃CH₂S(O)₂— andCF₃CF₂S(O)₂—.

The total number of carbon atoms in a substituent group is indicated bythe “C_(i)-C_(j)” prefix where i and j are integers. For example, C₁-C₄alkylsulfonyl designates methylsulfonyl through butylsulfonyl.

When a compound is substituted with a substituent bearing a subscriptthat indicates the number of said substituents can exceed 1, saidsubstituents (when they exceed 1) are independently selected from thegroup of defined substituents, e.g., (R₂)_(n), n is 1 or 2. “Aromatic”indicates that each of the ring atoms is essentially in the same planeand has ap-orbital perpendicular to the ring plane, and in which (4n+2)π electrons, where n is a positive integer, are associated with the ringto comply with H{umlaut over (ν)}ckel's rule.

The terms “heterocyclyl”, “heterocyclic ring” or “heterocycle” denote aring in which at least one atom forming the ring backbone is not carbon,e.g., nitrogen, oxygen sulfur or a group S(O) or S(O₂). Typically aheterocyclic ring contains no more than 4 nitrogens, no more than 2oxygens and no more than 2 sulfurs. In addition, the heterocyclic ringmay contain a group —C(O)—, —S(O)— or —S(O₂)—. Unless otherwiseindicated, a heterocyclic ring can be a saturated, partiallyunsaturated, or fully unsaturated ring. When a fully unsaturatedheterocyclic ring satisfies H{umlaut over (ν)}ckel's rule, then saidring is also called a “heteroaromatic ring” or “heteroaryl” substituent.Unless otherwise indicated, heterocyclic rings and ring systems can beattached through any available carbon or nitrogen by replacement of ahydrogen on said carbon or nitrogen.

The term heterocyclyl, either alone or in compound words such asheterocyclyloxy may be, for example a 5- or 6-membered heterocyclicradical having from 1 to 4, preferably from 1 to 3 same or differentheteroatoms selected from the group consisting of N, O and S, which isfurther unsubstituted or substituted.

The term heterocyclyl may denote, for example, a 5- or 6-memberedheteroaryl radical having from 1 to 4, preferably from 1 to 3 same ordifferent heteroatoms selected from the group consisting of N, O and S,which is further unsubstituted or substituted by one or moresubstituents as mentioned below. The heteroaryl radical is preferablysubstituted by 0 to 3, in particular 0, 1 or 2 substituents from thegroup as defined below.

Examples of suitable substituents of the heteroaryl are halogen,hydroxy, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, cyano, nitro, amino, N-mono-or N,N-di-C₁-C₆-alkylamino, C₃-C₆-cycloalkylamino, COOH,C₁-C₆-alkoxycarbonyl, C₂-C₆-alkylcarbonyl, C₁-C₆-alkylcarbonylamino,aminocarbonyl, N-mono- or N,N-di-C₁C₆-alkylaminocarbonyl, aminosulfonyl,or N-mono- or N,N, di-C₁-C₄-alkylaminosulfony.

Examples of a 5- or 6-membered heteroaryl radicals include a thienyl,pyrryl, furyl, oxazolyl, thiazolyl, pyridyl or pyrimidinyl radical whichis each unsubstituted or substituted, for example, by halogen,C₁-C₂-alkyl, C₁-C₂-haloalkyl, C₃-C₆-cycloalkyl or C₁-C₄-alkoxycarbonyl.

The term heterocyclyl may further denote a 3 to 6-memberedheterocycloalkyl radical having from 1 to 3 same or differentheteroatoms selected from the group consisting of N, O and S, which isfurther unsubstituted or substituted by one or more substituents asdefined above for heterocyclyl. The heterocycloalkylene radical ispreferably substituted by 0 to 3, in particular 0, 1 or 2 substituentsfrom the group as defined above. Examples are tetrahydrofuranyl,pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl which is eachunsubstituted or substituted by halogen, C₁-C₂-alkyl, C₁-C₂-haloalkyl orC₁-C₂-alkoxy.

Examples of heterocyclyloxy are 2-, 3- or 4-pyridyloxy orpyrimidin-4-yloxy, which is each unsubstituted or substituted byhalogen, C₁-C₂-alkyl, C₃-C₆-cycloalkyl, C₁-C₂-haloalkyl or C₁-C₂-alkoxy.

Examples of C₆-C₈-benzoheterocyclyl are benzoxazolyl, benzthiazolyl orindolyl, which may each be unsubstituted or substituted, for example, byhalogen, C₁-C₂-alkyl, C₁-C₂-haloalkyl or C₁-C₂-alkoxy.

Concerning the variables contained in the compounds of formula (I), thefollowing meanings and preferences apply.

The variable m is preferably an integer from 1 to 4, more preferably aninteger 1, 2 or 3, even more preferably an integer 1 or 2 and inparticular 1.

Each R is independently preferably halogen; C₁-C₄-alkyl;C₁-C₄-haloalkyl; amino; C₁-C₄-alkoxy; C₁-C₄-haloalkoxy;C₁-C₄-haloalkylthio; C₁-C₄-alkylsulfonyl; C₁-C₄-haloalkylsulfonyl;tri-C₁-C₂-alkylsilyl; C₁-C₄-alkoxycarbonyl; N-mono- orN,N-di-C₁-C₄-alkylaminocarbonyl; aminosulfonyl; N-mono- orN,N-di-C₁-C₄-alkylaminosulfonyl;N—C₁-C₂-alkyl-N—C₁-C₄-alkoxycarbonylamino; cyano; nitro; or 5- or6-membered hetero-cycloalkyl comprising 1 or 2 same or differentheteroatoms selected from O, S and N, which is unsubstituted orsubstituted by halogen, C₁-C₂-alkyl, C₁-C₂-haloalkyl or C₁-C₂-alkoxy.

Each R is independently more preferably halogen; C₁-C₂-alkyl;C₁-C₄-haloalkyl; amino; C₁-C₄-alkoxy; C₁-C₄-haloalkoxy;C₁-C₄-alkylsulfonyl; C₁-C₄-haloalkylsulfonyl; trimethylsilyl;C₁-C₄-alkoxycarbonyl; N,N-di-C₁-C₂-alkylaminocarbonyl; aminosulfonyl;N,N-di-C₁-C₂-alkylaminosulfonyl;N—C₁-C₂-alkyl-N—C₁-C₄-alkoxycarbonylamino; cyano; nitro; or aheterocycloalkyl radical selected from the group consisting oftetrahydrofuranyl, pyrrolidinyl, morpholinyl and piperidinyl.

Each R is independently particularly preferably halogen, C₁-C₂-alkyl,C₁-C₂-haloalkyl, C₁-C₂-alkoxy, C₁-C₂-haloalkoxy or cyano, and especiallychlorine, fluorine or CF₃. Specific preferred substituents (R)_(m) are2-, 3- or 4-Cl, 4-CF₃, 3,5-di-Cl, 3,5-di-CF₃, 2,4,6-tri-Cl,3,4,5-tri-Cl, 2-Cl-4-CF₃, 2-CF₃-4-Cl, 2,6-di-Cl-4-CF₃, in particular4-Cl.

The variable r is preferably an integer 1, 2 or 3 and more preferably 2or 3.

Each R¹ is independently preferably halogen; C₁-C₄-alkyl;C₁-C₄-haloalkyl; C₃-C₆-cycloalkyl; C₁-C₄-alkoxy; C₁-C₄-haloalkoxy;C₁-C₄-haloalkylthio; SF₅;N,N-di-C₁-C₄-alkylamino-C₁-C₄-alkylaminocarbonyl;N—C₁-C₄-alkylsulfonylamino; cyano; nitro; hydroxy; B(OH)₂, morpholino;or phenyl, benzoyl, pyridyloxy, pyrimidinyloxy or benzothiazloyl, whichis each unsubstituted or substituted by halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl or C₁-C₄-alkoxy.

Each R¹ is independently more preferably halogen; C₁-C₂-alkyl;C₁-C₃-haloalkyl; C₁-C₂-alkoxy; C₁-C₃-haloalkoxy; C₁-C₂-haloalkylthio;SF₅; nitro or hydroxy.

Each R¹ is independently particularly preferably halogen, methyl,C₁-C₃-haloalkyl, methoxy, C₁-C₃-haloalkoxy, SCF₃, SF₅, nitro or hydroxyand especially halogen or CF₃. Specific preferred substituents (R)_(m)are 3,4,5-tri-Cl, 3,5-di-CF₃-4-Cl, 3,5-di-CF₃.

According to one preferred embodiment of the invention r is an integer1, 2 or 3, and each R¹ is independently halogen; C₁-C₂-alkyl;C₁-C₃-haloalkyl; C₁-C₂-alkoxy; C₁-C₃-haloalkoxy; C₁-C₂-haloalkylthio;SF₅; nitro or hydroxy. According to one particularly preferredembodiment of the invention r is an integer 2 or 3, and each R¹ isindependently halogen; or C₁-C₃-haloalkyl.

The variable X preferably denotes O.

R⁰ is preferably H or methyl, in particular H.

One embodiment of the present invention concerns a compound of formula

wherein R, R⁰, R¹, m and r each have the above given meanings includingthe preferences. A preferred embodiment relates to a compound of formula(Ia), wherein R⁰ is H, m is 1, 2 or 3, especially 1 or 2, r is 2 or 3,especially 2, and for R and R¹ each the above-given meanings andpreferences apply. A particular preferred embodiment relates to acompound of formula (Ia), wherein R⁰ is H, m is 1 or 2, r is 2 or 3,each R is independently halogen, C₁-C₂-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylsulfonyl, trimethylsilyl,N,N-di-C₁-C₂-alkylaminosulfonyl,N—C₁-C₂-alkyl-N—C₁-C₄-alkoxycarbonylamino, cyano, nitro, orpyrrolidinyl, and each R¹ is independently C₁-C₄-haloalkyl. Anespecially preferred embodiment relates to a compound of formula (Ia),wherein R⁰ is H, m is 1 or 2, r is 2, each R is independently halogen orCF₃, and R¹ is CF₃.

A preferred embodiment of the present invention concerns a compound offormula

wherein for R and m each the above given meanings and preferences apply.

A further embodiment of the present invention concerns a compound offormula

wherein for R, R¹, m and r each the above given meanings and preferencesapply. A preferred embodiment relates to a compound of formula (Ib),wherein m is 1 or 2, especially 1, r is 2 or 3, and for R and R¹ eachthe above-given meanings and preferences apply. A particular preferredembodiment relates to a compound of formula (Ia), wherein m is 1, r is 2or 3, each R is halogen, C₁-C₃-haloalkyl, C₁-C₂-alkoxy or cyano, andeach R¹ is independently halogen, C₁-C₂-alkyl, C₁-C₃-haloalkyl,C₁-C₂-alkoxy, C₁-C₃-haloalkoxy, C₁-C₂-haloalkylthio, SF₅, nitro orhydroxy. An especially preferred embodiment relates to a compound offormula (Ib), wherein m is 1, r is 2 or 3, R is halogen or CF₃, inparticular chlorine, and each R¹ is halogen or CF₃.

A further preferred embodiment of the present invention concerns acompound of formula

wherein the variables a and b are each independently 0 or 1, (Hal) ishalogen, and R is halogen or CF₃, in particular halogen. In the aboveformula (Ib′) one of the variables a and b is preferably 1 and the otherone is 0 or 1.

A salt of a compound or formula (I) may be produced in known manner.Acid addition salts, for example, are obtainable by treatment with asuitable acid or a suitable ion exchange reagent, and salts with basesare obtainable by treatment with a suitable base or a suitable ionexchange reagent.

Salts of compounds of formula (I) can be converted into the freecompounds by the usual means, acid addition salts e.g. by treating witha suitable basic composition or with a suitable ion exchange reagent,and salts with bases e.g. by treating with a suitable acid or a suitableion exchange reagent.

Salts of compounds of formula (I) can be converted into other salts ofcompounds of the formula (I) in a known manner; acid addition salts canbe converted for example into other acid addition salts, e.g. bytreating a salt of an inorganic acid, such as a hydrochloride, with asuitable metal salt, such as a sodium, barium, or silver salt, of anacid, e.g. with silver acetate, in a suitable solvent, in which aresulting inorganic salt, e.g. silver chloride, is insoluble and thusprecipitates out from the reaction mixture.

Depending on the method and/or reaction conditions, the compounds offormula (I) with salt-forming characteristics can be obtained in freeform or in the form of salts. Compounds of formula (I) can also beobtained in the form of their hydrates and/or also can include othersolvents, used for example where necessary for the crystallisation ofcompounds present in solid form.

As mentioned before, the compounds of formula (I) may be optionallypresent as optical and/or geometric isomers or as a mixture thereof. Theinvention relates both to the pure isomers and to all possible isomericmixtures, and is hereinbefore and hereinafter understood as doing so,even if stereochemical details are not specifically mentioned in everycase.

Diastereoisomeric mixtures of compounds of formula (I), which areobtainable by the process or in another way, may be separated in knownmanner, on the basis of the physical-chemical differences in theircomponents, into the pure diastereoisomers, for example by fractionalcrystallisation, distillation and/or chromatography.

Splitting of mixtures of enantiomers, that are obtainable accordingly,into the pure isomers, may be achieved by known methods, for example byrecrystallisation from an optically active solvent, by chromatography onchiral adsorbents, e.g. high-pressure liquid chromatography (HPLC) onacetyl cellulose, with the assistance of appropriate micro-organisms, bycleavage with specific immobilised enzymes, through the formation ofinclusion compounds, e.g. using chiral crown ethers, whereby only oneenantiomer is complexed.

The compounds of the formula (I), wherein n is 0, may be prepared, forexample, by reaction of a compound of formula

wherein R⁰, R¹ and r are each as defined above and LG is a leavinggroup, for example halogen such as bromine, with a compound of formula

in the presence of a palladium catalyst, wherein R and m are each asdefined above. The details of this palladium-catalyzed carbon-carbonbond forming reaction, called Suzuki reaction, are known from textbooksof organic chemistry.

The compounds of formula (II) are known or may be prepared according toknown processes, for example by reacting a compound of formula

with a compound of formula

wherein LG′ is a leaving group, for example halogen, C₁-C₂-alkoxy orhydroxyl, and the further variables each have the above mentionedmeaning. The amide formation from an carboxylic acid or an derivativethereof with an amine is known from textbooks of organic chemistry. Thecompounds of formula (IV) are known or may be prepared according toknown processes, for example by reacting the corresponding amine withmethane sulfonyl chloride in known manner. The compounds of formula(III) and (V) are known compounds which are commercially available.

The compounds of the formula (I), wherein n is 1 and X is O, may beprepared, for example, by reaction of a compound of formula

with a compound of formula

wherein the variables are as defined above, followed by the reduction ofthe nitro group and further reacting the resulting amine with methanesulfonyl chloride. The details of these reactions are known fromtextbooks of organic chemistry. The compounds of formula (VI) may beprepared in analogy to the compounds of formula (II). The compounds offormula (VII) are known per se and are commercially available.

The compounds of the formula (I), wherein n is 1 may also be prepared byreaction of a compound of formula

with a compound of formula

wherein the variables each have the above given meaning, followed by thereduction of the nitro group and further reacting the resulting aminewith methane sulfonyl chloride. In the alternative, the nitro group ofthe compound of formula (VIII) may first of all be reduced and theresulting amino group be reacted with methane sulfonyl chloride, beforethe reaction with the compound of formula (V) is performed.

The compounds of formula (VIII) may be prepared in a manner known perse, for example by reaction of a compound of formula

with a compound of formula

yielding a compound of formula

which may, for example, be further transformed to a compound of formula

by the action with a strong base such as lithium hydroxide in an aqueousmedium.

The Examples further illustrate the different synthesis methods.

The compounds of formula (I) according to the invention are notable fortheir broad activity spectrum and are valuable active ingredients foruse in pest control, including in particular the control ofendoparasites, especially helminths, in and on warm-blooded animals,especially productive livestock and pets, whilst being well-tolerated bywarm-blooded animals and fish.

Productive livestock includes mammals such as, for example, cattle,horses, sheep, pigs, goats, donkeys, rabbits, deer, as well as birds,for example chickens, geese, turkeys, ducks and exotic birds.

Pets include, for example, dogs, cats and hamsters, in particular dogsand cats.

The compounds of formula (I) of the present invention are effectiveagainst helminths, in which the endoparasitic nematodes and trematodesmay be the cause of serious diseases of mammals and poultry. Typicalnematodes of this indication are: Filariidae, Setariidae, Haemonchus,Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris,Bunostonum, Oesophagostonum, Charbertia, Trichuris, Strongylus,Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia,Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. Thetrematodes include, in particular, the family of Fasciolideae,especially Fasciola hepatica.

It could also be shown surprisingly and unexpectedly that thecompositions of the present invention have exceptionally high efficacyagainst nematodes that are resistant to many active substances. This canbe demonstrated, for example in vitro by the LDA test.

Certain pests of the species Nematodirus, Cooperia and Oesophagostonuminfest the intestinal tract of the host animal, while others of thespecies Haemonchus and Ostertagia are parasitic in the stomach and thoseof the species Dictyocaulus are parasitic in the lung tissue. Parasitesof the families and may be found in the internal cell tissue and in theorgans, e.g. the heart, the blood vessels, the lymph vessels and thesubcutaneous tissue. A particularly notable parasite is the heartworm ofthe dog, Dirofilaria immitis.

The compounds of formula (I) according to the present invention arehighly effective against these parasites.

The pests which may be controlled by the compounds of formula (I) of thepresent invention also include those from the class of Cestoda(tapeworms), e.g. the families Mesocestoidae, especially of the genusMesocestoides, in particular M. lineatus; Dipylidiidae, especiallyDipylidium caninum, Joyeuxiella spp., in particular Joyeuxiellapasquali, and Diplopylidium spp., and Taeniidae, especially Taeniapisiformis, Taenia cervi, Taenia ovis, Taenia hydatigena, Taeniamulticeps, Taenia taeniaeformis, Taenia serialis, and Echinococcus spp.,most preferably Taenia hydatigena, Taenia ovis, Taenia multiceps, Taeniaserialis; Echinococcus granulosus and Echinococcus multilocularis.

Furthermore, the compounds of formula (I) are suitable for the controlof human pathogenic parasites. Of these, typical representatives thatappear in the digestive tract are those of the genus Ancylostoma,Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris andEnterobius. The compounds of the present invention are also effectiveagainst parasites of the genus Wuchereria, Brugia, Onchocerca and Loafrom the family of Dracunculus and parasites of the genus Strongyloidesand Trichinella, which infect the gastrointestinal tract in particular.

The good endoparasiticidal activity of the compounds of formula (I)corresponds to a mortality rate of at least 50-60%, in particular atleast 80% and especially at least 90% of the endoparasites mentioned.

Administration of the compounds of formula (I) according to theinvention may be effected therapeutically or preferablyprophylactically.

Application of the compounds of formula (I) according to the inventionto the animals to be treated may take place, for example, topically,perorally, parenterally or subcutaneously. A preferred embodiment of theinvention relates to compounds of formula (I) for parenteral use or, inparticular, for peroral use.

Preferred application forms for usage on warm-blooded animals in thecontrol of nematodes/helminths comprise solutions; emulsions includingclassical emulsions, microemulsions and self-emulsifying compositions,that are waterless organic, preferably oily, compositions which formemulsions—together with body fluids—upon addition to an animal body;suspensions (drenches); pour-on formulations; food additives; powders;tablets including effervescent tablets; boli; capsules includingmicro-capsules; and chewable treats; whereby the physiologicalcompatibility of the formulation excipients must be taken intoconsideration. Particularly preferred application forms are tablets,capsules, food additives or chewable treats.

The compounds of formula (I) of the present invention are employed inunmodified form or preferably together with adjuvants conventionallyused in the art of formulation and may therefore be processed in a knownmanner to give, for example, emulsifiable concentrates, directlydilutable solutions, dilute emulsions, soluble powders, powder mixtures,granules or microencapsulations in polymeric substances. As with thecompositions, the methods of application are selected in accordance withthe intended objectives and the prevailing circumstances.

The formulation, i.e. the agents, preparations or compositionscontaining the one or more active ingredients and optionally a solid orliquid adjuvant, are produced in a manner known per se, for example byintimately mixing and/or grinding the active ingredients with theadjuvants, for example with solvents, solid carriers and/orsurface-active compounds (surfactants).

The solvents in question may be: alcohols, such as ethanol, propanol orbutanol, and glycols and their ethers and esters, such as propyleneglycol, dipropylene glycol ether, ethylene glycol, ethylene glycolmonomethyl or -ethyl ether, ketones, such as cyclohexanone, isophoroneor diacetanol alcohol, strong polar solvents, such asN-methyl-2-pyrrolidone, dimethyl sulfoxide or dimethylformamide, orwater, vegetable oils, such as rape, castor, coconut, or soybean oil,and also, if appropriate, silicone oils.

Suitable surfactants are, for example, non-ionic surfactants, such as,for example, nonylphenolpolyethoxyethanols; castor oil polyglycolethers, for example macrogol glycerolhydroxystearate 40; polyethyleneglycols; polypropylene/polyethylene oxide adducts; or fatty acid estersof polyoxyethylene sorbitan, e.g. polyoxyethylene sorbitan monooleate.

Solid carriers, for example for tablets and boli, may be chemicallymodified polymeric natural substances that are soluble in water or inalcohol, such as starch, cellulose or protein derivatives (e.g. methylcellulose, carboxymethyl cellulose, ethylhydroxyethyl cellulose,proteins such as zein, gelatin and the like), as well as syntheticpolymers, such as polyvinyl alcohol, polyvinyl pyrrolidone etc. Thetablets also contain fillers (e.g. starch, microcrystalline cellulose,sugar, lactose etc.), glidants and disintegrants.

If the anthelminthics are present in the form of feed concentrates, thenthe carriers used are e.g. performance feeds, feed grain or proteinconcentrates. Such feed concentrates or compositions may contain, apartfrom the active ingredients, also additives, vitamins, antibiotics,chemotherapeutics or other pesticides, primarily bacteriostats,fungistats, coccidiostats, or even hormone preparations, substanceshaving anabolic action or substances which promote growth, which affectthe quality of meat of animals for slaughter or which are beneficial tothe organism in another way.

Suitable compositions of the compounds of formula (I) may also containfurther additives, such as stabilisers, antioxidants, for exampletocopherols like α-tocopherol, anti-foaming agents, viscosityregulators, binding agents, colors or tackifiers, as well as otheractive ingredients, in order to achieve special effects. Preferably, thecomposition comprises from 0.001 to 1% w/v of one or more antioxidants.If desired, the formulations of the present invention may comprise acolor, for example in an amount of from 0.001 to 1% w/v.

As a rule, an anthelminthic composition according to the inventioncontains 0.1 to 99% by weight, especially 0.1 to 95% by weight of acompound of formula (I), 99.9 to 1% by weight, especially 99.8 to 5% byweight of a solid or liquid admixture, including 0 to 25% by weight,especially 0.1 to 25% by weight of a surfactant.

In each of the processes according to the invention for pest control orin each of the pest control compositions according to the invention, thecompounds of formula (I) can be used in all of their stericconfigurations or in mixtures thereof.

The invention also includes a method of prophylactically protectingwarm-blooded animals, especially productive livestock and pets, inparticular dogs or cats, against parasitic helminths, which ischaracterised in that a compound of formula (I) or the active ingredientformulation prepared therefrom is administered to the warm-bloodedanimal as an additive to the feed, or to the drinks or also in solid orliquid form, orally or by injection or parenterally. The invention alsoincludes the compounds of formula (I) according to the invention forusage in one of the said processes.

The compounds of formula (I) according to the invention may be usedalone or in combination with other biocides. They may be combined withpesticides having the same sphere of activity e.g. to increase activity,or with substances having another sphere of activity e.g. to broaden therange of activity. It can also be sensible to add so-called repellents.

The following Examples illustrate the invention further.

Analysis of the purified samples is in each case done using a WatersAutopurification (HPLC/MS) system with a reversed phase column usingmethod B described below. The samples are characterized by m/z andretention time. The above-given retention times relate in each case tothe use of a solvent system comprising two different solvents, solventA: H₂O+0.01% HCOOH, and solvent B: CH₃CN+0.01% HCOOH).

-   -   Method B: column Waters XTerra MS C18 5 μm, 50×4.6 mm (Waters),        flow rate of 3.00 mL/min with a time-dependent gradient as given        in the Table:

Time [min] A [%] B [%] 0 90 10 0.5 90 10 2.5 5 95 2.8 5 95 2.9 90 10 3.090 10

Example 1 Synthesis ofN-(3,5-bis(trifluoromethyl)phenyl)-2′-chloro-4-(methyl-sulfonamido)-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamide(Ex. 1.13 in Table 1) Step A: Methyl 5-bromo-2-(methylsulfonamido)benzoate

A N₂ degassed solution of methyl 2-amino-5-bromobenzoate (2.8 g) in 10mL 1 pyridine was cooled to 0° C. before the drop wise addition ofmethane sulfonyl chloride (0.9 mL). The reaction mixture was stirredovernight at rt, then diluted with 50 mL ethyl acetate. The organiclayer was washed with a saturated solution of Na₂CO₃, with brine, thendried over MgSO₄ and evaporated to dryness (yield: 82%). LCMS (methodB): 305.6 (M−H)⁻ at 1.55 min.

Step B: 5-Bromo-2-(methylsulfonamido)benzoic acid

Methyl 5-bromo-2-(methylsulfonamido) benzoate (3.15 g) was suspended inTHF (20 mL, 1/1). NaOH 4 N (6.9 mL) was added and the reaction mixturewas stirred 4 h at reflux. Upon completion, the reaction mixture wastreated with 2N HCl (1 mL) and extracted twice with ethyl acetate.Combined organic layers were washed with H₂O, brine, dried over Na₂SO₄,filtered and evaporated to dryness. The title product was pure enough byLCMS to be engaged into next step without further purification. (yield:66%) LCMS (method B): 291.64 (M−H)⁻ at 1.2 min.

Step C:N-(3,5-bis(trifluoromethyl)phenyl)-5-bromo-2-(methylsulfonamido)benzamide

5-Bromo-2-(methylsulfonamido) benzoic acid (2.4 g) was treated withthionyl chloride (23 mL) at reflux for 4 h. Excess SOCl₂ was removedunder vacuum. CH₂Cl₂ (20 mL) was added to the acyl chloride. At 0° C.,3,5-bis(trifluoromethyl)aniline (1.4 mL) and NEt₃ (5.68 mL) in 10 mLCH₂Cl₂ were added slowly. The reaction mixture was allowed to warm upand it was stirred at rt overnight. The reaction mixture was dilutedwith 30 mL CH₂Cl₂. 20 mL HCl 2 N and 20 mL H₂O were added, and themixture was stirred until a yellow precipitate is formed. Theprecipitate was filtered off and dried under high vacuum before analysis(yield: 67%).

LCMS (method B): 502.93 (M−H)⁻ at 1.99 min.

Step D: Synthesis ofN-(3,5-bis(trifluoromethyl)phenyl)-2′-chloro-4-(methyl-sulfonamido)-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamide

To a solution of N-(3,5-bis(trifluoromethyl)phenyl)-5-bromo-2-(methylsulfonamido) benzamide (0.5 g) and2-Chloro-4(trifluoromethyl)benzeneboronic acid (286 mg) under N₂ indioxane/H₂O (4 mL, 1/1) was added Na₂CO₃ (636 mg) and(1,1′-bis-diphenylphosphino-ferrocene)palladium-II-dichloride(Pd(dppf)Cl₂.CH₂Cl₂, 366 mg).

The reaction mixture was stirred for 1 h at 85° C. It was diluted withethyl acetate, filtered through celite. The filtrate was washed withH₂O, brine, dried over Na₂SO₄, filtered and evaporated to dryness.

The crude mixture was purified by flash chromatography eluting with agradient of 100% heptane to 60% heptane/40% ethyl acetate to offer thetitle compound in 37% yield.

LCMS (method C): 604.7 (M+H)⁺ at 2.32 min.

The substances named in the following Table 1 are prepared analogouslyto the above-described method. The compounds are of formula

wherein the meaning of (R)_(m), is given in Table 1.

The following physical data are obtained according to theabove-described HPLC/MS characterization process.

TABLE 1 Ex. m/z: R_(t) [min] Physical No. (R)_(m) [M+H⁺] (Method) state1.1 4-CF₃ 570.7 2.27 (B) Powder 1.2 2,5-di-Cl 570.6 2.34 (B) Powder 1.33-(pyrrolidin-1-y1) 571.8 2.40 (B) Powder 1.4 4-N-tert-butoxycarbon-631.7 2.32 (B) Powder yl,N-methylamino 1.5 3,5-di-Cl 570.8 2.40 (B)Powder 1.6 2-F-3-Cl 554.7 2.25 (B) Powder 1.7 3-NO₂-4-methyl 561.7 2.17(B) Powder 1.8 3-Si(CH₃)₃ 574.7 2.53 (B) Solid 1.9 3,5-di-CH₃ 530.8 2.33(B) Powder 1.10 2,3,4,5-tetra-F 574.8 2.20 (B) Powder 1.11 4-CN 527.72.01 (B) Powder 1.12 3-CF₃-4-Cl 604.7 2.34 (B) Foam 1.13 2-Cl-4-CF₃604.7 2.32 (B) Powder 1.14 3,5-di-CF₃ 638.7 2.38 (B) Powder 1.154-isopropylsulfonyl 608.7 1.98 (B) Powder 1.163-N,N-diethylaminocarbonyl 601.8 2.00 (B) Powder 1.17 3-N,N-dimethylaminosulfonyl 609.9 1.97 (B) Foam 1.183-trifluoromethoxy-5-amino 601.9 2.10 (B) Powder 1.19 3,4,5-tri-Cl 604.72.52 (B) Powder 1.20 4-pentafluoroethoxy 636.9 2.43 (B) Powder 1.213,4,5-tri-F 556.9 2.20 (B) Powder 1.22 2,4,6-tri-Cl 604.8 2.36 (B)Powder 1.23 2,6-di-Cl-4-CF₃ 638.8 2.34 (B) Powder 1.24 3-CF₃-4-Br 614.82.30 (B) Powder 1.25 2-Cl-4-CF₃ 682.7 2.42 (B) Solid 1.26 2,4,6-tri-CH₃543.01 2.36 (B) Foam (M − H)−

Example 25-(4-Chlorophenoxy)-2-(methylsulfonamido)-N-(3,4,5-trichlorophenyl)benzamide (Ex. 2.1 in Table 2) Step A:5-Chloro-2-nitro-N-(3,4,5-trichlorophenyl) benzamide

5-chloro-2-nitrobenzoic acid (10 g) was treated with thionyl chloride(7.2 mL) at reflux for 4 h. Excess SOCl₂ was removed under vacuum.CH₂Cl₂ (100 mL) was added to the acyl chloride. At 0° C.,3,4,5-trichloroaniline (9.7 g) and NEt₃ (13.8 mL) in 100 mL CH₂Cl₂ wereadded slowly. The reaction mixture was allowed to warm up and it wasstirred at room temperature (RT) overnight.

The reaction mixture was diluted with 200 mL diethyl ether. 10 mL HCl 2N and 200 mL H₂O were added, and the mixture was stirred until a yellowprecipitate is formed. The precipitate was filtered off and dried underhigh vacuum before analysis (yield: 66%).

LCMS (method B): 380.59 (M+H)⁺ at 1.97 min.

Step B: 5-(4-Chlorophenoxy)-2-nitro-N-(3,4,5-trichlorophenyl) benzamide

5-Chloro-2-nitro-N-(3,4,5-trichlorophenyl) benzamide (8.77 g), K₂CO₃(6.7 g) and 4-chlorophenol (3.26 g) in DMA were heated at 140° C. during14 h. The reaction mixture was poured in H₂O (100 mL), the precipitatewas filtered off, dried under high vacuum to afford a brown solid(yield: 55%).

LCMS (method B): 468.45 (M−H)⁻ at 2.25 min.

Step C: 2-Amino-5-(4-chlorophenoxy)-N-(3,4,5-trichlorophenyl) benzamide

Under N₂, 5-(4-chlorophenoxy)-2-nitro-N-(3,4,5-trichlorophenyl)benzamide (13.2 g) in 80 mL EtOH/H₂O (3/1) was treated with Fe (10.9 g)and HCl 25% (0.6 mL) and the reaction mixture was stirred at RT for 4 h.When the reduction was completed, the reaction mixture was filtered on aplug of celite and washed with ethyl acetate. The filtrate wasevaporated under vacuum. Ethyl acetate was added, and the organic layerwas washed with brine, dried over MgSO₄, and evaporated to dryness(yield: 89%).

LCMS (method B): 442.54 (M+H)⁺ at 2.41 min.

Step D:5-(4-Chlorophenoxy)-2-(methylsulfonamido)-N-(3,4,5-trichlorophenyl)benzamide

To N₂ degassed solution of2-amino-5-(4-chlorophenoxy)-N-(3,4,5-trichlorophenyl) benzamide (9 g) in50 mL of CH₂Cl₂, pyridine (8.2 mL) was added. The mixture was cooled to0° C. before the drop wise addition of methane sulfonyl chloride (1.6mL). The reaction mixture was stirred overnight at RT, then diluted withadditional 50 mL CH₂Cl₂. The organic layer was washed with a saturatedsolution of Na₂CO₃, with brine, then dried over MgSO₄ and evaporated todryness (yield: 81%).

LCMS (method B): 518.5 (M+H)⁺ at 2.27 min.

Example 3 5-((4-Chlorophenyl) (cyano)methyl)-2-(methylsulfonamido)-N-(3, 4, 5-trichlorophenyl) benzamide (Ex.2.7 in Table 2) Step A: Methyl 5-((4-chlorophenyl) (cyano)methyl)-2-nitrobenzoate

NaH (140 mg) was suspended in 10 mL DMF. 2-(4-chlorophenyl) acetonitrile(600 mg) in 2 mL DMF was added drop wise at 0° C. to the reactionmixture, then allowed to stir at rt for 2 h. The mixture was cooled to0° C. before adding drop wise methyl 5-chloro-2-nitrobenzoate (1.024 g)dissolved in 1.5 mL DMF. The reaction was stirred 2 h at 0° C., thenovernight at RT. Diisopropyl ether was added, and the mixture was washedwith H₂O, brine, dried over Na₂SO₄, filtered and evaporated to dryness.The crude product was purified on a semi-preparative HPLC to offer thetitle compound in 12% yield.

LCMS (method B): 328.84 (M−H)⁻ at 1.75 min.

Step B: Methyl 2-amino-5-((4-chlorophenyl) (cyano) methyl) benzoate

Methyl 5-((4-chlorophenyl) (cyano) methyl)-2-nitrobenzoate was reducedin a similar manner as step C of Example 2 (yield: 96%).

LCMS (method B): 300.88 (M+H)⁺ at 1.72 min.

Step C: Methyl 5-((4-Chlorophenyl) (cyano) methyl)-2-(methylsulfonamido)benzoate

Methyl 2-amino-5-((4-chlorophenyl) (cyano) methyl) benzoate wassulfonylated in a similar manner as step D of Example 2 (yield: 55%).

LCMS (method B): 376.76 (M−H)⁻ at 1.71 min.

Step D: 5-((4-Chlorophenyl) (cyano) methyl)-2-(methylsulfonamido)benzoic acid

Methyl 5-((4-chlorophenyl)(cyano)methyl)-2-(methylsulfonamido)benzoate(50 mg) was suspended in MeOH/H₂O (1 mL, 1/1). NaOH (6 mg) was added andthe reaction mixture was stirred overnight at RT. Upon completion, thereaction mixture was treated with 2N HCl (1 mL) and extracted twice withEthyl acetate. Combined organic layers were washed with H₂O, brine,dried over Na₂SO₄, filtered and evaporated to dryness. The title productwas pure enough by LCMS to be engaged into next step without furtherpurification.

LCMS (method B): 362.71 (M−H)⁻ at 1.52 min.

Step E:5-((4-Chlorophenyl)(cyano)methyl)-2-(methylsulfonamido)-N-(3,4,5-trichloro-phenyl)benzamide

5-((4-chlorophenyl) (cyano) methyl)-2-(methylsulfonamido) benzoic acid(48 mg) was dissolved in CH₂Cl₂ (1.5 mL). 3,4,5 trichloroaniline (31mg), benzotriazol-1-yl-oxytri-pyrrolidinophosphonium hexafluorophosphate(Pybop, 75 mg), and diisopropylethylamine (DIPEA, 69 L) were added. Thereaction mixture was stirred at RT overnight. H₂O was added and themixture was extracted with CH₂Cl₂. Combined organic layers were washedwith saturated solution of Na₂CO₃, brine, filtered and evaporated todryness. The crude product was purified on a semi-preparative HPLC tooffer the title compound in 46% yield.

LCMS (method B): 539.58 (M−H)⁻ at 2.15 min.

Example 45-(4-Chlorobenzoyl)-2-(methylsulfonamido)-N-(3,4,5-trichlorophenyl)benzamide(Ex. 2.6 in Table 2) Step A: 5-(4-Chlorobenzoyl)-2-nitrobenzoic acid

Methyl 5-((4-chlorophenyl)(cyano)methyl)-2-nitrobenzoate (150 mg, seeStep A Example 3) was treated with LiOH (6 eq.) in THF/H₂O (4/1, 5 mL)at rt overnight. Additional 6 eq. of LiOH were added. The reaction wascompleted after 72 h. HCl 2N was added until reaching pH 1-2, and thenthe reaction mixture was extracted twice with ethyl acetate. Combinedorganic layers were washed with H₂O, brine, dried over Na₂SO₄, filteredand evaporated to dryness. The title compound was pure enough for use instep B.

LCMS (method B): 303.85 (M−H)⁻ at 1.54 min.

Step B: 5-(4-Chlorobenzoyl)-2-nitro-N-(3,4,5-trichlorophenyl)benzamide

5-(4-Chlorobenzoyl)-2-nitrobenzoic acid was treated in a similar manneras described Example 3, step E (yield: 71%).

LCMS (method B): 480.57 (M−H)⁻ at 2.20 min.

Step C: 2-Amino-5-(4-chlorobenzoyl)-N-(3,4,5-trichlorophenyl)benzamide

5-(4-Chlorobenzoyl)-2-nitro-N-(3,4,5-trichlorophenyl)benzamide wastreated in a similar manner as described in Example 3, step B (yield:93%).

LCMS (method B): 450.61 (M−H)⁻ at 2.31 min.

Step D:5-(4-Chlorobenzoyl)-2-(methylsulfonamido)-N-(3,4,5-trichlorophenyl)benzamide

2-Amino-5-(4-chlorobenzoyl)-N-(3,4,5-trichlorophenyl)benzamide wastreated in a similar manner as described in Example 2, step D (yield:18%).

LCMS (method B): 530.5 (M+H)⁺ at 2.23 min.

The substances named in the following Table 2 are prepared analogouslyto the above-described methods. The compounds are of formula

wherein the meaning of (R¹)_(r), (R)_(m), and X are given in Table 2

The following physical data are obtained according to theabove-described HPLC/MS characterization process.

TABLE 2 Ex. m/z: R_(t) [min] R_(t) [min] No. (R)_(m) (R¹)_(r) X [M + H⁺](Method) (Method) 2.1 4-Cl 3,4,5-tri-Cl O 518.5 2.27 (B) Solid 2.2 H3,4,5-tri-Cl O 484.6 2.16 (B) Powder 2.3 4-Cl 3,4,5-tri-Cl NH 517.5 2.13(B) Powder 2.4 4-Cl 3,4,5-tri-Cl S 534.5 2.38 (B) Solid 2.5 H3,4,5-tri-Cl NH 483.7 1.98 (B) Solid 2.6 4-Cl 3,4,5-tri-Cl C(O) 530.62.23 (B) Solid 2.7 4-Cl 3,4,5-tri-Cl C(CN) 541.5 2.15 (B) Foam 2.8 4-Br3,5-di-CF₃ O 596.9 2.23 (B) Foam 2.9 4-CN 3,5-di-CF₃ O 543.9 1.98 (B)Gum 2.10 3,5-di-CF₃ 3,5-di-CF₃ O 654.9 2.31 (B) Solid 2.11 2-Cl3,5-di-CF₃ O 552.9 2.19 (B) Gum 2.12 3-Cl 3,5-di-CF₃ O 552.9 2.14 (B)Solid 2.13 4-CF₃ 3,5-di-CF₃ O 586.9 2.22 (B) Oil 2.14 3-OCH₃ 3,5-di-CF₃CH═CH 558.8 2.21 (B) Solid 2.15 4-Cl 3,4-di-Cl O 484 2.11 (B) Solid [M −H]⁻ 2.16 4-Cl 4-OCF₃ O 500.7 2.03 (B) Powder 2.17 4-Cl 3-CF₃-4-OCH₃ O514.6 1.94 (B) Powder 2.18 4-Cl 4-SF₅ O 542.5 2.04 (B) Solid 2.19 4-Cl3,4,5-tri-F O 470.6 1.96 (B) Solid 2.20 4-Cl 3-B(OH)₂ O 460.7 2.01 (B)Oil 2.21 4-Cl 3-CF₃-4-Br O 562.5 2.10 (B) Oil 2.22 4-Cl4-CF(CF₃)₂-2,6-di-CH₃ O 612.7 2.18 (B) Oil 2.23 4-Cl 2,3,4-tri-Cl O518.6 2.12 (B) Oil 2.24 4-Cl 4-cyclohexyl O 498.8 2.35 (B) Oil 2.25 4-Cl4-OCF₂CHFCF₃-2,5- O 650.6 2.19 (B) Solid di-Cl 2.26 4-Cl 3,5-di-CF₃ O552.6 2.14 (B) Solid 2.27 4-Cl 3-CF₃-4-Cl O 518.6 2.09 (B) Solid 2.284-Cl 4-NO₂-2-Cl O 495.6 1.93 (B) Oil 2.29 4-Cl 4-SCF₃ O 516.7 2.17 (B)Oil 2.30 4-Cl 2,4,5-tri-F O 470.7 1.93 (B) Oil 2.31 4-Cl 3,5-di-F-4-Cl O486.7 2.10 (B) Oil 2.32 4-Cl 2-(N-morpholino) O 501.8 1.97 (B) Oil 2.334-Cl 2,3,4-tri-F O 470.8 1.96 (B) Oil 2.34 4-Cl 3,4-di-F O 452.8 2.00(B) Oil 2.35 4-Cl 3,5-di-F O 452.8 2.02 (B) Foam 2.36 4-Cl 2,3,5-tri-F O470.8 1.99 (B) Foam 2.37 4-Cl 3,5-di-Cl-4-F O 502.7 2.21 (B) Oil 2.384-Cl 3,5-di-Cl O 484.7 2.23 (B) Oil 2.39 4-Cl 4-NO₂ O 461.8 2.42 (B)Powder 2.40 4-Cl 3-Cl-4-Br O 528.7 2.15 (B) Solid 2.41 4-Cl2-(N,N-diethylamino)- O 559.0 1.21 (B) Oil ethyl-aminocarbonyl 2.42 4-Cl3-Cl-4-J O 576.6 2.17 (B) Oil 2.43 4-Cl 2-F-4-Br O 512.7 2.00 (B)Crystal 2.44 4-Cl 3,4-di-Br O 572.6 2.14 (B) Solid 2.45 4-Cl3,5-di-Cl-4-Br O 562.6 2.19 (B) Oil 2.46 4-Cl 3,5-di-Cl-4-CH₃ O 498.82.30 (B) Oil 2.47 4-Cl 3,5-di-Cl-4-OH O 500.6 1.83 (B) Oil 2.48 4-Cl3,5-di-CF₃-4-Br O 630.5 2.30 (B) Solid 2.49 4-Cl 3,5-di-Cl-4-OCH₃ O514.6 2.12 (B) Foam 2.50 4-Cl 4-CF(CF₃)₂ O 584.8 2.23 (B) Foam 2.51 4-Cl3-CF₃ O 484.9 2.03 (B) Foam 2.52 4-Cl 3-OCF₃ O 500.8 2.06 (B) Foam 2.534-Cl 3-CHF₂ O 466.8 1.90 (B) Foam 2.54 4-Cl 3-SF₅ O 542.9 1.97 (B)Powder 2.55 4-Cl 4-CF₃ O 484.8 2.04 (B) Powder 2.56 4-Cl 3,5-di-CF₃-4-ClO 586.8 2.28 (B) Powder 2.57 4-Cl 3,5-di-Cl-2-OH O 500.6 1.94 (B) Oil2.58 4-Cl 2-CH₃SO₂NH-4,5-di-Cl O 577.7 1.89 (B) Powder

The substances named in the following Table 3 are prepared analogouslyto the above-described methods. The compounds are of formula

wherein the meaning Y is given in Table 3. The following physical dataare obtained according to the above-described HPLC/MS characterizationprocess.

TABLE 3 Ex. m/z: R_(t) [min] R_(t) [min] No. Y [M + H⁺] (Method)(Method) 3.1 

577.7 2.09 (B) Powder 3.2 

711.6 2.34 (B) Powder 3.3 

618.8 2.22 (B) Powder 3.4 

584.7 2.19 (B) Solid 3.5 

563.8 2.38 (B) Solid 3.6 

492.9 2.18 (B) Solid 3.7 

481.8 1.91 (B) Solid 3.8 

492.8 1.98 (B) Solid 3.9 

492.8 2.10 (B) Solid 3.10

522.8 2.14 (B) Solid

Biological Examples: Gastro-Intestinal Larval Development Assay

Freshly harvested and cleaned nematode eggs are used to seed a suitablyformatted well plate containing the test substances to be evaluated forantiparasitic activity and media allowing the full development of eggsthrough to 3rd instar larvae. The plates are incubated for 6 days at 25°C. and 60% relative humidity. Egg-hatching and ensuing larvaldevelopment are recorded to identify a possible nematodicidal activity.Efficacy is expressed in percent reduced egg hatch, reduced developmentof L3, or paralysis & death of larvae at any stage. Compounds Nos.1.9-1.13, 1.21-1.23, 1.25, 1.26, 2.13, 2.50, 2.51 and 2.54 reached ≧60%efficacy at 10 ppm, and are therefore considered active.

Dirofilaria immitis Microfilaria Assay

Freshly harvested and cleaned Dirofilaria immitis microfilariae areprepared from blood from donor animals dogs. The microfilariae are thendistributed in formatted microplates containing the test substances tobe evaluated for antiparasitic activity. The plates are incubated for 48hours at 25° C. and 60% relative humidity (RH). Motility ofmicrofilariae is then recorded to determine efficacy. Efficacy isexpressed in percent reduced motility as compared to the control andstandards. Compounds Nos. 1.1-1.25, 2.1-2.58, and 3.1-3.10 showed anefficacy above 50% at 10 ppm, and are therefore considered active.

Acanthocheilonema viteae in Gerbil

Gerbils are artificially infected with 80 L3 larvae of A. viteae bysubcutaneous injection. Treatment by gavage with the formulated testcompounds occurs consecutively day 5 to day 9 after infection.Eighty-four days after infection, gerbils are bled for countingcirculating microfilariae, using a Fuchs-Rosenthal counting chamber andmicroscope. Only test groups with an average of circulatingmicrofilariae at least 50% lower than in the placebo treated group arefully dissected to recover adult worms. Efficacy is expressed as a %reduction in worm numbers in comparison with the placebo treated group,using the Abbot's formula. Compound No. 1.5, 1.10, 1.13, 1.17, 2.1,2.21, 2.26 and 2.51 showed an efficacy above 80% at 10 mg/kg.

Adult Liver Fluke-In Vitro Assay

Freshly harvested adult Fasciola hepatica from cattle or sheep liverswere distributed in 12-well plates (1 fluke per well) with 4 mL of RPMIcomplete medium and kept in an incubator at 37° C. for approximately 12hours. After renewal of the medium, the viability of the flukes isdetermined by video-registration of the movement of the individualflukes (pre-value). Test compounds are added at a concentration of 100μg/mL and the movements of the flukes are measured after 6 and 24 hours.Efficacy is expressed as percent reduced movement based on the pre-valueand the untreated control. In this test the following examples showedmore than >90% efficacy after 6 h and >95% after 24 h are considered aspositive: 1.5, 1.10, 1.13, 2.19, 2.21, 2.26, and 2.48.

1. A compound of formula

or a salt or an enantiomer thereof, wherein X is O, S, NR²C(O), C(CN) orCH═CH, R⁰ is H, C₁-C₄-alkyl or hydroxyl; n is 0 or 1, each R isindependently halogen; C₁-C₆-alkyl; C₁-C₆-haloalkyl; C₃-C₆-cycloalkyl;C₃-C₆-halocycloalkyl; amino; N-mono- or N,N-di-C₁-C₄-alkylamino;hydroxy; C₁-C₆-alkoxy; C₁-C₆-haloalkoxy; C₁-C₆-alkylthio;C₁-C₆-haloalkylthio; C₁-C₆-alkyl sulfinyl; C₁-C₆-haloalkylsulfinyl;C₁-C₆-alkylsulfonyl; C₁-C₆-haloalkylsulfonyl; SF₅; tri-C₁-C₄-alkylsilyl;C₁-C₆-alkoxycarbonyl; aminocarbonyl; N-mono- orN,N-di-C₁-C₆-alkylaminocarbonyl; aminosulfonyl; N-mono- orN,N-di-C₁-C₆-alkylaminosulfonyl; N—C₁-C₆-alkylsulfonylamino;C₁-C₆-alkoxycarbonylamino; N—C₁-C₄-alkyl-N— C₁-C₆-alkoxycarbonylamino;cyano; nitro; or C₃-C₆-heterocyclyl which is unsubstituted orsubstituted by halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cyclolalkyl,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, amino, cyano or nitro; m is an integerfrom 0 to 4; each R¹ is independently halogen; C₁-C₆-alkyl;C₁-C₆-haloalkyl; C₃-C₆-cycloalkyl; C₃-C₆-halocycloalkyl; C₁-C₆-alkoxy;C₁-C₆-haloalkoxy; C₁-C₆-alkylthio; C₁-C₆-haloalkylthio;C₁-C₆-alkyl-sulfinyl; C₁-C₆-haloalkylsulfinyl; C₁-C₆-alkylsulfonyl;C₁-C₆-haloalkylsulfonyl; SF₅; amino; N-mono- or N,N-di-C₁-C₆-alkylamino;tri-C₁-C₄-alkylsilyl; C₁-C₆-alkoxycarbonyl; aminocarbonyl; N-mono- orN,N-di-C₁-C₆-alkylaminocarbonyl;N,N-di-C₁-C₄-alkylamino-C₁-C₄-alkylaminocarbonyl; aminosulfonyl; N-mono-or N,N-di-C₁-C₆-alkylaminosulfonyl; N—C₁-C₆-alkylsulfonylamino;C₁-C₆-alkoxycarbonylamino; N—C₁-C₄-alkyl-N—C₁-C₆-alkoxycarbonylamino;cyano; nitro; hydroxy; B(OH)₂; or phenyl, benzoyl, C₃-C₆-heterocyclyl,C₃-C₆-heterocyclyloxy or C₆-C₈-benzoheterocyclyl, which is eachunsubstituted or substituted by halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₃-C₆-cycloalkyl; C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, amino, cyano or nitro;and r is an integer of from 1 to
 4. 2. A compound of formula (I)according to claim 1, wherein each R is independently halogen;C₁-C₄-alkyl; C₁-C₄-haloalkyl; amino; C₁-C₄-alkoxy; C₁-C₄-haloalkoxy;C₁-C₄-haloalkylthio; C₁-C₄-alkylsulfonyl; C₁-C₄-haloalkylsulfonyl;tri-C₁-C₂-alkylsilyl; C₁-C₄-alkoxycarbonyl; N-mono- orN,N-di-C₁-C₄-alkylaminocarbonyl; aminosulfonyl; N-mono- orN,N-di-C₁-C₄-alkylaminosulfonyl;N—C₁-C₂-alkyl-N—C₁-C₄-alkoxycarbonylamino; cyano; nitro; or 5- or6-membered heterocycloalkyl comprising 1 or 2 same or differentheteroatoms selected from O, S and N, which is unsubstituted orsubstituted by halogen, C₁-C₂-alkyl, C₁-C₂-haloalkyl or C₁-C₂-alkoxy. 3.A compound of formula (I) according to claim 1, wherein each R ishalogen, C₁-C₂-alkyl, C₁-C₂-haloalkyl, C₁-C₂-alkoxy, C₁-C₂-haloalkoxy orcyano, in particular chlorine, fluorine or CF₃.
 4. A compound of formula(I) according to claim 3, wherein m is an integer 1, 2 or 3, preferably1 or 2, and in particular
 1. 5. A compound of formula (I) according toclaim 4, wherein each R¹ is independently halogen; C₁-C₄-alkyl;C₁-C₄-haloalkyl; C₃-C₆-cycloalkyl; C₁-C₄-alkoxy; C₁-C₄-haloalkoxy;C₁-C₄-haloalkylthio; SF₅;N,N-di-C₁-C₄-alkylamino-C₁-C₄-alkylaminocarbonyl;N—C₁-C₄-alkylsulfonylamino; cyano; nitro; hydroxy; B(OH)₂, morpholino;or phenyl, benzoyl, pyridyloxy, pyrimidinyloxy or benzothiazloyl, whichis each unsubstituted or substituted by halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl or C₁-C₄-alkoxy.
 6. A compound offormula (I) according to claim 4, wherein each R¹ is independentlyhalogen; C₁-C₂-alkyl; C₁-C₃-haloalkyl; C₁-C₂-alkoxy; C₁-C₃-haloalkoxy;C₁-C₂-haloalkylthio; SF₅; nitro; or hydroxy; and in particular halogenor CF₃.
 7. A compound of formula (I) according to claim 6, wherein r isan integer of 1, 2 or 3, in particular 2 or
 3. 8. A compound of formula(I) according to claim 7, wherein R⁰ is H, m is 0 or 1 and X is O.
 9. Acompound according to claim 1 of formula

wherein R and m are each as defined in claim
 1. 10. A compound accordingto claim 1 of formula

wherein R, R¹, m and r are each as defined in claim
 1. 11. A compound offormula (Ib) according to claim 10, wherein m is an integer 1 or 2, r isan integer 2 or 3, each R is independently halogen or CF₃, and each R¹is independently halogen or CF₃.
 12. Composition for the control ofparasites, which contains as active ingredient at least one compound offormula (I) according to claim 1, in addition to carriers and/ordispersants.
 13. A compound of formula (I) according to claim 1 for usein the control of endoparasites in or on warm-blooded animals. 14.Method of controlling endoparasites, on warm-blooded animals, whichcomprises administering to the warm-blooded animals a veterinaryeffective amount of at least one compound of formula (I) according toclaim
 1. 15. Use of a compound of formula (I) according to claim 1 inthe preparation of a veterinary or pharmaceutical composition againstendoparasites in or on warm-blooded animals